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The American Journal of Emergency... Aug 2023Rapid-sequence intubation (RSI) is the process of administering a sedative and neuromuscular blocking agent (NMBA) in rapid succession to facilitate endotracheal... (Review)
Review
PURPOSE
Rapid-sequence intubation (RSI) is the process of administering a sedative and neuromuscular blocking agent (NMBA) in rapid succession to facilitate endotracheal intubation. It is the most common and preferred method for intubation of patients presenting to the emergency department (ED). The selection and use of medications to facilitate RSI is critical for success. The purpose of this review is to describe pharmacotherapies used during the RSI process, discuss current clinical controversies in RSI medication selection, and review pharmacotherapy considerations for alternative intubation methods.
SUMMARY
There are several steps to the intubation process requiring medication considerations, including pretreatment, induction, paralysis, and post-intubation sedation and analgesia. Pretreatment medications include atropine, lidocaine, and fentanyl; but use of these agents in clinical practice has fallen out of favor as there is limited evidence for their use outside of select clinical scenarios. There are several options for induction agents, though etomidate and ketamine are the most used due to their more favorable hemodynamic profiles. Currently there is retrospective evidence that etomidate may produce less hypotension than ketamine in patients presenting with shock or sepsis. Succinylcholine and rocuronium are the preferred neuromuscular blocking agents, and the literature suggests minimal differences between succinylcholine and high dose rocuronium in first-pass success rates. Selection between the two is based on patient specific factors, half-life and adverse effect profiles. Finally, medication-assisted preoxygenation and awake intubation are less common methods for intubation in the ED but require different considerations for medication use.
AREAS FOR FUTURE RESEARCH
The optimal selection, dosing, and administration of RSI medications is complicated, and further research is needed in several areas. Additional prospective studies are needed to determine optimal induction agent selection and dosing in patients presenting with shock or sepsis. Controversy exists over optimal medication administration order (paralytic first vs induction first) and medication dosing in obese patients, but there is insufficient evidence to significantly alter current practices regarding medication dosing and administration. Further research examining awareness with paralysis during RSI is needed before definitive and widespread practice changes to medication use during RSI can be made.
Topics: Humans; Succinylcholine; Etomidate; Rocuronium; Rapid Sequence Induction and Intubation; Ketamine; Retrospective Studies; Hypnotics and Sedatives; Emergency Service, Hospital; Neuromuscular Blocking Agents; Intubation, Intratracheal
PubMed: 37196592
DOI: 10.1016/j.ajem.2023.05.004 -
Journal of Critical Care Oct 2023We performed a meta-analysis of randomized controlled trials to evaluate if etomidate impacted mortality in critically ill adults when compared with other induction... (Meta-Analysis)
Meta-Analysis
PURPOSE
We performed a meta-analysis of randomized controlled trials to evaluate if etomidate impacted mortality in critically ill adults when compared with other induction agents.
MATERIALS AND METHODS
We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials which compared etomidate with any other induction agent in critically ill adult patients undergoing endotracheal intubation. The primary outcome was mortality at the main timepoint defined by the study. We conducted a fixed-effects meta-analysis for the risk ratio. Using that risk ratio and 95% confidence interval, we then estimated the probability of any harm (RR > 1) and the number needed to harm ≤100 (RR ≥ 1.05).
RESULTS
We included 11 randomized trials comprising 2704 patients. We found that etomidate increased mortality (319/1359 [23%] vs. 267/1345 [20%]; risk ratio (RR) = 1.16; 95% confidence interval (CI), 1.01-1.33; P = 0.03; I = 0%; number needed to harm = 31). The probabilities of any increase and a 1% increase (NNH ≤100) in mortality were 98.1% and 92.1%, respectively.
CONCLUSIONS
This meta-analysis found a high probability that etomidate increases mortality when used as an induction agent in critically ill patients with a number needed to harm of 31.
Topics: Adult; Humans; Etomidate; Critical Illness; Randomized Controlled Trials as Topic; Intubation, Intratracheal
PubMed: 37127020
DOI: 10.1016/j.jcrc.2023.154317 -
Signal Transduction and Targeted Therapy Nov 2023Glioma is the most prevalent brain tumor, presenting with limited treatment options, while patients with malignant glioma and glioblastoma (GBM) have poor prognoses. The...
Glioma is the most prevalent brain tumor, presenting with limited treatment options, while patients with malignant glioma and glioblastoma (GBM) have poor prognoses. The physical obstacle to drug delivery imposed by the blood‒brain barrier (BBB) and glioma stem cells (GSCs), which are widely recognized as crucial elements contributing to the unsatisfactory clinical outcomes. In this study, we found a small molecule, gambogic amide (GA-amide), exhibited the ability to effectively penetrate the blood-brain barrier (BBB) and displayed a notable enrichment within the tumor region. Moreover, GA-amide exhibited significant efficacy in inhibiting tumor growth across various in vivo glioma models, encompassing transgenic and primary patient-derived xenograft (PDX) models. We further performed a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen to determine the druggable target of GA-amide. By the combination of the cellular thermal shift assay (CETSA), the drug affinity responsive target stability (DARTS) approach, molecular docking simulation and surface plasmon resonance (SPR) analysis, WD repeat domain 1 (WDR1) was identified as the direct binding target of GA-amide. Through direct interaction with WDR1, GA-amide promoted the formation of a complex involving WDR1, MYH9 and Cofilin, which accelerate the depolymerization of F-actin to inhibit the invasion of patient-derived glioma cells (PDCs) and induce PDC apoptosis via the mitochondrial apoptotic pathway. In conclusion, our study not only identified GA-amide as an effective and safe agent for treating glioma but also shed light on the underlying mechanisms of GA-amide from the perspective of cytoskeletal homeostasis.
Topics: Humans; Molecular Docking Simulation; Cell Line, Tumor; Glioma; Cytoskeleton; Amides; Microfilament Proteins
PubMed: 37935665
DOI: 10.1038/s41392-023-01666-3 -
Nature Feb 2024Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics...
Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4 T cells and agonism of the pregnane X receptor. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.
Topics: Animals; Humans; Bifidobacterium; Bile Acids and Salts; CD4-Positive T-Lymphocytes; Clostridium; Cohort Studies; Crohn Disease; Enterococcus; Esters; Fatty Acids; Inflammatory Bowel Diseases; Metabolomics; Phenotype; Pregnane X Receptor; Reproducibility of Results; Tandem Mass Spectrometry; Amides
PubMed: 38052229
DOI: 10.1038/s41586-023-06906-8 -
Sedative Dose for Rapid Sequence Intubation and Postintubation Hypotension: Is There an Association?Annals of Emergency Medicine Oct 2023For patients with hemodynamic instability undergoing rapid sequence intubation, experts recommend reducing the sedative medication dose to minimize the risk of further...
STUDY OBJECTIVE
For patients with hemodynamic instability undergoing rapid sequence intubation, experts recommend reducing the sedative medication dose to minimize the risk of further hemodynamic deterioration. Scant data support this practice for etomidate and ketamine. We sought to determine if the dose of etomidate or ketamine was independently associated with postintubation hypotension.
METHODS
We analyzed data from the National Emergency Airway Registry from January 2016 to December 2018. Patients aged 14 years or older were included if the first intubation attempt was facilitated with etomidate or ketamine. We used multivariable modeling to determine whether drug dose in milligrams per kilogram of patient weight was independently associated with postintubation hypotension (systolic blood pressure < 100 mm Hg).
RESULTS
We analyzed 12,175 intubation encounters facilitated by etomidate and 1,849 facilitated by ketamine. The median drug doses were 0.28 mg/kg (interquartile range [IQR] 0.22 mg/kg to 0.32 mg/kg) for etomidate and 1.33 mg/kg (IQR 1 mg/kg to 1.8 mg/kg) for ketamine. Postintubation hypotension occurred in 1,976 patients (16.2%) who received etomidate and in 537 patients (29.0%) who received ketamine. In multivariable models, neither the etomidate dose (adjusted odds ratio [aOR] 0.95, 95% confidence interval [CI] 0.90 to 1.01) nor ketamine dose (aOR 0.97, 95% CI 0.81 to 1.17) was associated with postintubation hypotension. Results were similar in sensitivity analyses excluding patients with preintubation hypotension and including only patients intubated for shock.
CONCLUSION
In this large registry of patients intubated after receiving either etomidate or ketamine, we observed no association between the weight-based sedative dose and postintubation hypotension.
Topics: Humans; Hypnotics and Sedatives; Etomidate; Rapid Sequence Induction and Intubation; Ketamine; Intubation, Intratracheal; Retrospective Studies; Hypotension
PubMed: 37389494
DOI: 10.1016/j.annemergmed.2023.05.014 -
Methods in Molecular Biology (Clifton,... 2024This protocol describes the application of cyclotron-generated [C]CO fixation reactions for direct C-carboxylation reactions and [C]CO for C-carbonylations. Herein we...
This protocol describes the application of cyclotron-generated [C]CO fixation reactions for direct C-carboxylation reactions and [C]CO for C-carbonylations. Herein we describe one-pot methods wherein the radioactive gas is first trapped in a reaction mixture at room temperature and atmospheric pressure prior to the radiolabeling reactions. Such procedures are widely applicable to numerous small molecules to form C-labeled carboxylic acids, amides, esters, ketones, oxazolidinones, carbamates, and ureas. The steps for C-fixation techniques described herein are tailored for a commercial automated synthesis unit and are readily adapted for routine radiopharmaceutical production.
Topics: Carbon Radioisotopes; Carbon Dioxide; Amides; Urea; Carboxylic Acids
PubMed: 38006487
DOI: 10.1007/978-1-0716-3499-8_1 -
Current Opinion in Anaesthesiology Aug 2023This review summarizes the current indications and principles of ECT. Contemporary anesthetic considerations are described with a focus on the optimal use of hypnotic... (Review)
Review
PURPOSE OF REVIEW
This review summarizes the current indications and principles of ECT. Contemporary anesthetic considerations are described with a focus on the optimal use of hypnotic agents and providing ECT in pregnant patients.
RECENT FINDINGS
ECT is useful in treatment-resistant major depression, bipolar disorders, and treatment-resistant schizophrenia. It is a well tolerated treatment in pregnant patients with treatment-resistant depression. Cognitive side effects may be attenuated by using unilateral placement of scalp electrodes, fewer treatment sessions, and the use of ultrabrief pulse width of the electrical charge. All modern hypnotics can be used for induction of anesthesia for ECT but should be titrated to effect. Etomidate is superior to Propofol in regarding seizure quality. The use of Ketamine shows good seizure quality and may alleviate cognitive impairment. Providing ECT for pregnant patients may prove challenging because of logistic difficulties and the physiologic changes during pregnancy. Although representing an effective treatment option in severely ill patients, ECT is underutilized because of stigmatization and ethnic and financial disparities.
SUMMARY
ECT is effective in treating treatment-resistant psychiatric illnesses. Symptoms of cognitive impairment are the most common side effects but can be treated by modifying the technique of ECT. All modern hypnotics can be used for the induction of general anesthesia. Etomidate and Ketamine may be of special interest in patients with insufficient seizure duration. Treating pregnant patients with ECT requires a multidisciplinary approach, in order to provide a safe therapy for mother and unborn child. Stigmatization and social disparities are hindering the widespread use of ECT as an effective treatment for severely ill psychiatric patients.
Topics: Humans; Electroconvulsive Therapy; Ketamine; Anesthetics, Intravenous; Etomidate; Hypnotics and Sedatives; Anesthesia, General; Seizures; Treatment Outcome
PubMed: 37314167
DOI: 10.1097/ACO.0000000000001279 -
Critical Care (London, England) Feb 2024Tracheal intubation is a high-risk intervention commonly performed in critically ill patients. Due to its favorable cardiovascular profile, ketamine is considered less... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tracheal intubation is a high-risk intervention commonly performed in critically ill patients. Due to its favorable cardiovascular profile, ketamine is considered less likely to compromise clinical outcomes. This meta-analysis aimed to assess whether ketamine, compared with other agents, reduces mortality in critically ill patients undergoing intubation.
METHODS
We searched MEDLINE, Embase, and the Cochrane Library from inception until April 27, 2023, for randomized controlled trials and matched observational studies comparing ketamine with any control in critically ill patients as an induction agent. The primary outcome was mortality at the longest follow-up available, and the secondary outcomes included Sequential Organ Failure Assessment score, ventilator-free days at day 28, vasopressor-free days at day 28, post-induction mean arterial pressure, and successful intubation on the first attempt. For the primary outcome, we used a Bayesian random-effects meta-analysis on the risk ratio (RR) scale with a weakly informative neutral prior corresponding to a mean estimate of no difference with 95% probability; the estimated effect size will fall between a relative risk of 0.25 and 4. The RR and 95% credible interval (CrI) were used to estimate the probability of mortality reduction (RR < 1). The secondary outcomes were assessed with a frequentist random-effects model. We registered this study in Open Science Framework ( https://osf.io/2vf79/ ).
RESULTS
We included seven randomized trials and one propensity-matched study totaling 2978 patients. Etomidate was the comparator in all the identified studies. The probability that ketamine reduced mortality was 83.2% (376/1475 [25%] vs. 411/1503 [27%]; RR, 0.93; 95% CrI, 0.79-1.08), which was confirmed by a subgroup analysis excluding studies with a high risk of bias. No significant difference was observed in any secondary outcomes.
CONCLUSIONS
All of the included studies evaluated ketamine versus etomidate among critically ill adults requiring tracheal intubation. This meta-analysis showed a moderate probability that induction with ketamine is associated with a reduced risk of mortality.
Topics: Adult; Humans; Etomidate; Ketamine; Bayes Theorem; Critical Illness; Intubation, Intratracheal
PubMed: 38368326
DOI: 10.1186/s13054-024-04831-4 -
Current Eye Research Aug 2023To investigate the biochemical characteristics in experimental keratomycosis.
PURPOSE
To investigate the biochemical characteristics in experimental keratomycosis.
METHODS
Experimental mice were injected with solution Controls mice received liposomes containing phosphate-buffered saline (PBS-LIP). Raman spectroscopy was used to analyze the biochemical characteristics. The infiltration of inflammatory cells was analyzed by histopathology. Cytokine mRNA levels were detected by real-time polymerase chain reaction.
RESULTS
Raman Spectroscopy: In the experimental group, collagen, lipids, amide I and III were decreased, amide II, hyper proline amino acids, and arginine were increased, and proline and phenylalanine were significantly increased on day 3. Histopathology: more severe keratomycosis developed in the experimental group than in the control group. Statistically significant mRNA expression of Collagen4\MMP2\MMP9\TIMP1.MMP9 was negatively correlated with the secretion of Collagen4.
CONCLUSIONS
Matrix metalloproteinases are involved in biochemical changes in keratomycosis.
Topics: Mice; Animals; Matrix Metalloproteinase 9; Corneal Ulcer; Eye Infections, Fungal; RNA, Messenger; Amides; Proline
PubMed: 37027008
DOI: 10.1080/02713683.2023.2199448 -
Endocrinology Aug 2023In this review, we provide the status of research on vasoactive intestinal peptide (VIP) and oxytocin, typical C-terminal α-amidated peptide hormones, including their... (Review)
Review
In this review, we provide the status of research on vasoactive intestinal peptide (VIP) and oxytocin, typical C-terminal α-amidated peptide hormones, including their precursor protein structures, processing and C-terminal α-amidation, and the recently identified mechanisms of regulation of oxytocin secretion and its transportation through the blood brain barrier. More than half of neural and endocrine peptides, such as VIP and oxytocin, have the α-amide structure at their C-terminus, which is essential for biological activities. We have studied the synthesis and function of C-terminal α-amidated peptides, including VIP and oxytocin, since the 1980s. Human VIP mRNA encoded not only VIP but also another related C-terminal α-amidated peptide, PHM-27 (peptide having amino-terminal histidine, carboxy-terminal methionine amide, and 27 amino acid residues). The human VIP/PHM-27 gene is composed of 7 exons and regulated synergistically by cyclic AMP and protein kinase C pathways. VIP has an essential role in glycemic control using transgenic mouse technology. The peptide C-terminal α-amidation proceeded through a 2-step mechanism catalyzed by 2 different enzymes encoded in a single mRNA. In the oxytocin secretion from the hypothalamus/the posterior pituitary, the CD38-cyclic ADP-ribose signal system, which was first established in the insulin secretion from pancreatic β cells of the islets of Langerhans, was found to be essential. A possible mechanism involving RAGE (receptor for advanced glycation end-products) of the oxytocin transportation from the blood stream into the brain through the blood-brain barrier has also been suggested.
Topics: Mice; Humans; Animals; Vasoactive Intestinal Peptide; Oxytocin; Peptide PHI; Receptor for Advanced Glycation End Products; Amides; Mice, Transgenic
PubMed: 37548257
DOI: 10.1210/endocr/bqad121